An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model.
An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model.
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DOI：
10.1101/gad.275891.115
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发表时间：
2016-04-15
影响因子：
10.5
通讯作者：
Murphy ME
中科院分区：
文献类型：
--
作者：
Jennis M;Kung CP;Basu S;Budina-Kolomets A;Leu JI;Khaku S;Scott JP;Cai KQ;Campbell MR;Porter DK;Wang X;Bell DA;Li X;Garlick DS;Liu Q;Hollstein M;George DL;Murphy ME
在这项研究中，Jennis等人描述了p53肿瘤抑制基因密码子47的非洲特异性自然编码区变异（S47）的第一个小鼠模型。他们表明，纯合子S47小鼠明显易患肿瘤，而且S47变异不仅损害p53介导的细胞死亡，还损害p53反激活参与代谢和铁下垂的一组基因的能力。非洲裔人群中存在TP53密码子47的非同义单核苷酸多态性（P47S, rs1800371；此处简称S47）。在这里，我们报道，在人类细胞系和小鼠模型中，与野生型p53相比，S47变体在大多数基因毒性应激下表现出适度的凋亡减少，但在顺铂诱导的细胞死亡中表现出明显的缺陷。我们发现，与野生型p53相比，S47具有几乎无法区分的转录功能，但显示出p53靶基因亚群的反激活能力受损，包括两个参与代谢的基因：Gls2（谷氨酰胺酶2）和Sco2。我们还表明，表达S47变体的人和小鼠细胞对诱导铁凋亡（铁介导的非凋亡细胞死亡）的药物的细胞死亡具有明显的抗性。我们发现纯合子或杂合子形式表达S47的小鼠易患不同组织学类型的自发性癌症。我们的数据表明，S47变异可能会增加非洲裔个体的癌症风险，我们的研究结果强调了评估该变异对这些人群癌症风险的贡献的必要性。这些数据也证实了代谢和铁下垂与p53抑制肿瘤的潜在相关性。
In this study, Jennis et al. characterize the first mouse model of an African-specific naturally occurring coding region variant at codon 47 of the p53 tumor suppressor gene (S47). They show that homozygous S47 mice are markedly tumor-prone and that the S47 variant impairs not only p53-mediated cell death but also the ability of p53 to transactivate a subset of genes involved in metabolism and ferroptosis. A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism: Gls2 (glutaminase 2) and Sco2. We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.